Steroido [3.2-d] pyrimidines and preparation thereof



This invention relates to heterocyclic Substituted steroids, and in particular it is concerned with steroido [3.2-d1pytimidines and the preparation thereof.

It has been found that new and useful compounds are produced when a pyrimidine ring is fused through its 4- and -positions to the 3- and 2-positions, respectively,

' known to exhibit hormonal or other pharmacological or steroid;

The steroid moiety can be any member of the estrane,

of a steroid nucleus, said steroid having from seventeen to about twenty-three carbon atoms exclusive 'of ester radicals. 1

The ring structure-of the compounds of the invention isnepre's'entedby the following structure:

. The exact natureof the steroid moiety is not critical,

T United States Patent 7 3,132,137 Patented May 5, 1964 ice ' normal steroid moieties in the compounds of the invention and it can be derived from any steroid of the general type endocrinolog'ical properties. Such steroid moieties have from seventeen to about twenty-three carbon atoms, not counting carbon content which may be provided by esterified hydroxy groups. Esterified hydroxysteroids are inchided within the scope of the invention, but the carbon content contributed by the acid moiety of the ester isnot considered part of the essential carbon content of the 18-norestrane, androstane, etiocholane, pregnane or allopregnane series. The foregoing can contain varying degrees of unsaturation and-a variety of substituents in the form of hydrocarbon radicalsor functional groups conventionally employed in the steroid-art. Representative of the steroid moieties which make up the compounds of the invention are those havingat position .17- a 11ydroxy, acyloxy,oxo, orboth a hydroxy and a lo'wer-all'ryl radical, characteristic of the androgenic and anabolic 'dr'oxyacetyL.1,2-dihydroxyethyl, l-hydroXyethyl, and the like radicals, characteristic of the progestational and adrenal cortical steroids. The steroid moiety can also :have

- one or more substituents at other positions of the nucleus, for example, hydroxy, acyloxy, or 0x0 radicals at positions1-, 4-, 5'-, 6-, 7-, 8-, 9-, ,11 12-, 14-, 15-01 16-:(the oxo groups being restrict'edto positions having secondary 8-, 9-, 11-, 12-, 14-, 15- or 16-po siti ons The steroid moiety can also have one or more double bonds, especiallyat the 4,5- and/or 1,2-and/or 6,7-positions. The

steroid moiety usually possesses angular methyl groups at lent of lower-alkanoamidine or acid-addition salt thereof steroids; or a lower-alkenyl, loWer-alkynyl, acetyl, hy-

G and Gig although 18- an'd19-norsteroids and 18,19-

bisnorster'oids, lacking one or both. of the angular methyl groups at C and C respectively, are also representative steroids.

about 50 C. and C.

contain, respectively, seventeen, eighteen and nineteen carbon atoms plus any carbon content'which may be provided by one or more nuclearly substituted carbon 7 molecular-weight less than about 200. Representative of the acyl radicals which canbe present are'lower-alkanoyl radicals, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, caproyl, heptanoyl, octanoyl, trimethylacetyl, and the like; carboXy-lower-alkanoyl radicals, e.g., succinyl (,B-carboxypropionyl); cycloalkyl-loWer-alkanoyl radicals, e.g., ,fi-cyclopentylpropionyl, fi-cyclohexylpropionyl, and the like; monocarbocyclic aroyl radicals, e.g., benzoyl, p-toluyl, p-nitrobenzoyl, 3,4,5-trimethoxybenzoyl, and the like; monocarbocyclic aryl-lower-alkanoyl or -alkenoyl radicals, such as phenylacetyl, 'fl-phenylpropionyl, cinnamoyl, and the like; ancl mono'carbocyclic aryloxy-loweralkanoyl radicals, such as p-chlorophenoxyacetyl, and the like. Esters of inorganic acids, for instance, phosphoric acid, are-also contemplated.

The compounds of the invention are prepared by reacting a with a lower-alkanoamidine or an acid-additionsalt'thereof in the presence of a basic tertiary amine or an] alkali metal alkoxide according to the following equation:

The condensation of the lower-alkanoamidine with. a

Z-hydroxy-lower-alky1idene-3-oxo-steroid can be carried out by heating said-steroid with atleast one molar equivain the presence of a basic tertiary amine or alkali metal alkoxide in aninert solvent at a temperature between If the steroid moiety hasa double bond already present in the 1,2-position, the essential steroid intermediate is a 2-forrny1-A -steroid (III; R is H) or a Z-lower-alkanoyl- A -steroid (III; R islower-alkyl). The reaction is represented by the following equation;

The intermediate 2-acyl-A steroid (III) can be prepared by bromination or, chlorination of a.2-acyl steroid (1) inthe '2-positioii, followed'by de'hydrohalogenation 2-(1-hydroxy-lower-alkylidene)-3-oXo-steroid Compounds having an aromatic ring A characteristic of the estrogens (estratriene compounds), viz.:

from readily available starting materials, comprises those having the structural formula wherein R and R each represents hydrogen or a loweralkyl radical; R represents hydrogen or a lower alkyl,

lower alkenyl, lower alkyny-l, the acetyl, the hydroxyacetyl, the 1,2-dihydroxyethyl or the l-h ydroxyethyl radical; X is selected from the group consisting of H (H)-(OII) and O; Y and Y represent hydrogen or the methyl radical; and Z represents hydrogen or the hydrouy radical, Z being restricted to hydroxy when R represents hydrogen, or a lower alkyl, lower-allmnyl or lower-alkynyl radical.- Antoher preferred aspect of the invention includes compounds differing from V in having a further double bond in the 4,5-position (VI), or in both the The preferred aspects also include carboxylic acid esters of compounds of structures V, VI and VII when carbinols,

pared by reacting the appropriate Z-(I-hydroxy-loweralkylidene) -3 oxosteroid, viz.

(VIII) or the corresponding compounds where double bonds are present in the 4,5- or the 4,5- and 6,7ap0siti0ns, with a lower-alkano-a-midine or an acidaaddition salt thereof; R, V

R, X, Z, Y and Y have the same meanings given above. When the steroid moiety contains oxo groups in addition to the one at position 3, these can be protected as ketal derivatives to prevent competing reactions. For example, when compounds in which R represents acetyl or hydroxyacetyl are desired, these radicals can be ketalized by known methods, e.-g., with ethylene glycol, prior to introduction of the hydroXy-lower-alkylidcne radical at the 2- position and reaction with a lower-alkanoamidine. It has been found, however, that 3,20-dioXo-steroids bearing hydroxy groups at the 17- and 21-positions can be selectively formylated in the 2-position without need for protecting the 20-:oiro group by ketalization.

The ZO-monoketals of 3,20-dioxo-steroids are prepared from the 3,20=diketals by selective hydrolysis by known methods, e.g., by allowing the diketal to stand at room temperature in acetone solution containing a trace of ptoluenesulfonic acid. The keta-l groups are readily cleaved by .dilute acid after the condensation with the lower alkanoamidine, An oxo group at the ll-position is relatively unreactive and need not be protected.

The present invention has provided a new class of steroid compounds, namely steroido[3.2 d] pyrimidines, and these compounds have now been made available for study as. to their endocrinological activities. Compounds of the invention have indeed been found to possess such activities as set forth below, and they are also useful as intermediates in the preparation of different species within the scope of the invention by introduction of new groups or alteration of groups already present in the steroid nucleus by known methods. For example, a steroido[3.2-d]pyrimidine having a hydrorry group in the 17-position of the steroid nucleus (V, VI or VII; R is H,

Z is OH) can be oxidized to the corresponding l7-oxo compound. As another instance, a steroido[3.2-d]pyrimidine having a l-hydroxyethyl radical in the 17-position elimination of a molecule of an alcohol as: follows;

Still another aspect includes acid-addition salts and q-ua- V ternary ammonium salts of the foregoing compounds.

In the above general IForrnulas V, VI and VII, R, when it represents a lowen'alkyl, lower-alkenyl, or lower-alkynyl radical, has from one ,to about tour carbon atoms and mayfibe straight or branched, and thus includes such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarybutyl, vinyl, l-propeny-l, Zpropenyl, ethyriyl, propargyl, and the like.

The compounds of Formulas V, VI and VII are prei p, I 12-00- nooon 1 I b n on In the case wherein the radical R is lower-alkyl an alternative and preferred method comprises treating the 3-oxoi steroid with a lower-allcanoic acid anhydride in the presence of' boron trifluoride. Steroidscontainiug a 17- hydroxy group, particularly the 17-hydr0xy-17-alkyl steroids, can be protected against 'dehydnation by prior esteriiication.

Although, by analogy with halogenation procedures, it would be expected that ring A saturated Compounds of the etiocholane series (ring juncture A/B cis) would form 4-hydroxy-lower-alkylidene derivatives rather than 2-hy- 'droXy-lower-alkylidene derivatives, it has been found that the latter are produced preponderantly. This was proved by preparing a A -steroido[3.2-c]pyrazole from a 2-hydroxy-methylene-A -steroid, according to the method described in the copending application of R. 0. Clinton, Serial No, 723,148, filed March 24, 1958, hydrogenating the double bond to produce a mixture of saturated steroido[3.2-c] pyrazoles of the androstane and etiocholane series, and showing that the etiocholane isomer wasiden tical with that produced by directformation of the pyraz ole from the hydroxymethylenederivative of the parent etiocholane compound. If the hydroxymethylene group had entered the 4-position, the resulting pyrazole would have been fused to the 3,4-position of the steroid nucleus and would have been different from the etiocholanopyrazole obtained by hydrogenation' of the A -compound. Therefore, etiocholane as well as androstane compounds are useful as starting materials in the preparation of the compounds of the invention. I

'Endocrinological studies of the compounds of the invention have shown that they possessuseful metabolic, hormonal and anti-hormonal properties. In particular, they have favorable balances of anabolic, androgenic, pituitary inhibiting, estrogenic, progestational andadrenal "cortical activities. Thus, compounds of the invention possess advantages in being anabolic (myotrophic and ni-' trogen retentive) at dose levels at which they do not show an appreciable degree of sex hormonal properties.

Anabolic agents. are useful in the alleviation of conditions arising frorn poor nitrogen utilization in various debilitating diseases by accelerating the growth of new healthy tissue. Generally speaking, the common anachloroform. The chloroform extracts were washed with bolic agents-possess a moderate to high degree of androgenic activity and their use in females leads to undesirable side-effects such as virilism and hirsutism. Therefore, the separation of these activities, as found in compounds of the present invention, which have. high anabolic but low androgenic activities, is a. highly desirable feature.

The .compounds of the inventionc'an. be prepared for use .by dispersing them in an aqueous suspension or by dissolvingthem ina pharmacologically acceptable oil :or oilwater emulsion for parenteral administration; or

by incorporation in tablet form with excipients for oral V administration. r

. The structure of the. compounds of the invention was established by the mode of synthesis, their ultraviolet and infrared spectra, and by the fact thatthe values found upon elementary analysis corresponded with the values calculated for the assigned structures. i

The following examples ,will further illustrate the invention Without the latter being limited thereby.

EXAMPLE 1 (a) 2 Hydro'xym ethylenef- 17a methylundrostan 17,6-0l3-0' ne',-A solution. (r201 g. v of 17a-methylan-; drostan-l7fiaol-3-one in 500 ml. of benzene was added to sqfliummethoxide (prepared by dissolving 15.0 g. of sodium in 250 ml. fofabsolute methanol, concentrating the isolution and drying'the residuefor onej hour at 150- a 160 C. and 15mm) Ethyl formate (48,8 g.) Was then 'added with stirring in a. nitrogen atmosphere. The re.- 3 action mixture was stirred for four hours longer at room temperature, allowed to stand for about fifteen hours,

stirred fortwo hours longer andthen poured into water. The reaction mixture was extracted with benzene, the aqueous layer warmed until clear, filtered. and cooled below room temperature; Concentrated hydrochloricacid and ice were added to. the filtrate until the mixture was acidto Congo. Red, and theproduct was extracted with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a volume of 80 1111., whereupon there separated 14.89 g. of .2-hydroxymethylene-17u-methylandrostan-l7fi-ol-3-one, M.P. 179183 C. (uncorr.). A sample when recrystallized from an ether-methanol mixture and dried at 80 C. in vacuo had the M.P. 185- 190.5 C. (corn), [a] =+35.9 (1% in chloroform); ultraviolet maximum at 282 m (E=l0,300).

Analysis.-Calcd. for 0 1-1 0 C, 75.86; H, 9.70. Found: C, 76.10; H, 9.53.

(12) 17,8 hydroxy 170; methylandr0stan0[3.2-d] 2-meth'ylpyrimidine [V;' R is H, R and R" are CH X is H Z is OH, Y and Y are CH (rings A/B trans)].--

A mixture of 6.65 g. of Z-hydrOxymethylene-l7a-methylandrostan-l7fl-ol-3-one, 2.30 g. of acetamidine hydrochloride, 3.45 ml. of triethylamine and 16 ml. of anhydrous ethanol was refluxed for twentyefour hours. The mixture was then dissolved in ether and the ether extracted with concentrated hydrochloric acid diluted with four volumes of water. The acidic aqueous extracts were made strongly basic by adding an excess of 35% sodium hydroxide solution, the basic mixture was extracted-With ether, and the ether solution dried over anhydrous sodium sulfate and concentrated to give 4.5 g. of "a mixture of 7 solid and orange oil. Ether was added and the solid removed by filtration. Benzene was added to the filtrate,

the filtrate concentrated to remove the ether, and the solution chromatographed on a column of 250 g. of Florisil1(activated magnesium silicate prepared according to US. Patent 2,393,625). The column was eluted with benzene and then with benzene containing gradually increasing amounts of ether. Eluants containing 15-20% ether in benzene brought out the desired product which was recrystallized twice from ethyl acetate and driedat 100 C. over phosphorus pentoxide for four hours to give 17p-hydroxy-17a-methylandrostano[3.2+d] 2'-methyl- V pyrimidine in the form of plate clusters, M.P. 161.2- 163.4 C. (corn); [a] =+31.7 (1% in chloroform); ultraviolet maximum at 260 m (E 4,500).

Analysis.-Calcd.' for C H N O:- C, 77.92; H, 9.67;

N, 7.90. Found: C, 77.52; H, 9.86; N, 7.82.

When measured by its effect upon the growthof the levator ani muscle in the rat, l7u-hydroxy-17a-methylandrostano[3.2-d]'-2'-methylpyrimidine was found to possess myotrophic activity witha low degree of androgenicity. It was active when administered either subcutaneously or orally.

1 EXAMPLE 2 (a) 2-hydroxymethyleneandrostan-J7fi-ol-3-0ne was prepared from androstan-17B-ol-3-one and ethyl formate in the presence of sodium methoXi-de in benzene solution. according to the manipulative procedure described above in Example 1, part (a). The product was re crystallized from acetone and ether, giving 2-hydroxymethyleneand-rostan-17,6-ol-3-one, M.P. 126132 C. (uncorn); ultraviolet maximum at 282 m (E 8,400).1

(b) 17,8 hydroxyandrostano[3.2-d]+2'-methylpyrimitime tv; R and R are H, R is CH3, X is H2, 2 is OH,

Y and Y are CH was prepared from 6.40 g. of hydroxyrnethyleneandrostan-l7fi-ol-3-one, 2.3 g. of acetamidine hydrochloride, 3.45 ml. of triethylamine and 16 1 ml. of anhydrous ethanol according to the manipulative procedure described above in Example 1,'pant (b). There was thus obtained l'lfi-hydroxyandrostano[324d]-2- .methylpyrimidine in the form of ,colorless'clusters, of

elongated prisms, M.P.163.4-165.2 C. (c'orr.) (reeiytallized from ethylacetate-hexane);[wha 456.2? (1% in chloroform); ultraviolet maxim-um -at 260 m (E=' Analysis.-Calcd. for C H gN O: 0,7760; H, 9.47; N, 8.23. Found: C, 77.76; H, 9.19; N, 7.87..

When measured by its effect upon the growth of the levator muscle in the rat, 17fi{hydroxyandrostano[3.2 dJ-Z-methylpyrirhidiue was found to possess myotrophic activity with a low degree of and rogenicity when adminis tered subcutaneously at a dose level of 11.2 mg./ kg./ day.

EXAMPLE 3 of colorless prisms, M.P. 205.6-207.2 C. (corn) (recrystallized from benzene); [a] =-|29'.7 (1% in chloroform); ultrayiolet maximum at 254 m (E=4,100).

Analysis.-Calcd. for C H N O: C, 77.60; H, 9.47; N, 8.23. Found: C, 77.43; H, 9.31; N, 8.01.

EXAMPLE 4 (a) 2 hydroxymethylene-I7a-methyl-4-andr0sten-17B- 0l-3-0ne.-To a dry 2 liter, 3-necked flask, fitted with a stopper, gas outlet stopcock and a condenser arranged tor distillation into a receiver equipped with a calcium chloride tube, was added a solution of 50.0 g. (0.165 mole) of 17amethyl-4-androsten-17B-ol-3-one in 1200 .ml. of benzene. A portion of the benzene (200 ml.)

was removed by distillation to insure anhydrous conditions. The distillation apparatus was replaced with an outlet tube connected to a gas trap which consisted of a U-tube filled with an amount of mercury that would allow the escape of .any positive pressure built up in the reaction flask. A slow stream of nitrogen was introduced into the reaction flask through the gas outlet stopcock.

Sodiumhydride (10.0 g., 0.42 mole) and ml. (0.43

mole) of ethyl formate, previously dried over phosphorus pentoxide and distilled, were added. The reaction mixture was allowed to stand at room temperature under a nitrogen atmosphere for five days, after which time an orange gel had formed and no further evolution of gas could be observed. The reaction flask was fitted with a mechanical stirrer, and 25 ml. of methyl alcohol was carefully added with stirring to decompose excess sodium hydride. The reaction mixture was poured into 1500 ml- .of water and shaken. The layers were separated, and

the aqueous layer was extracted with ether, cooled to ice bath temperature and acidified with concentrated bydrochloric acid containing ice. The solid product was collected by filtration, washed with water and dried at 60 C. for twenty-four hours in vacuo, giving 49.1 g. of 2-hydroxymethylene-17a-methyl-4-androsten-17,8-01-3- one. A sample when recrystallized from a methanolwater mixture had the M.P. 178.5-180" C. (corn),

[a] =+14.0 (1% in chloroform); ultraviolet maxim aat 252 and 307 mp. (E=l2,000 and 6,030).

Analysis.Calcd. for C H O C, 76.32; H, 9.15.

Found: C, 76.36; H, 9.19.

(b) 175 hydroxy-I7a-methyl-4-andr0sten0[3,24%]-2- methylpyrimidine [VI; R is H, R and R" are CH X is H Z is OH, Y and Y are CH can be prepared from 2 hydroxymethylene 17a-methyl-4 atndrosten-17,8-ol-3- one and acetamidine according to the manipulative procedure described above in Example 1, part (b).

EXAMPLE 5 (a) 2 hydroxymgthylene-4-androsten-17fi-0l-3-0ne was prepared from 25 g. of testosterone, 7.5 g. of sodium hydride and 25 ml. ofethyl formate in 500 of dry benzene according to the manipulative procedure described above in Example 4, part (a). There was thus obtained 21.63 g. of 2-hydroxyrnethylene-4-arrdrosten-17,8-ol-3:one in crystalline form. J (b) 176 acetoxy-4-androsteno[3.2rd]-2'-methylpyrim idine [VI; R and R are H, R is CH X is H Zis OCOCH Y andY' are CH ].'A mixture'of 3.16 g.

of 2-hydroxymethylene-4-androsten-l7,6-ol-3 one, 1.15 g. of alcetamidine' hydrochloride, 1.73 ml. of triethylamtine and 10 m1. of dimethyltormamide was refluxed for two hours. The crude product was isolated in the manner described above in Example 1, part (b) and acetylated by heating for twelve minutes with 4 ml. of pyridine and 4 ml. of acetic anhydride. The acetylated product was purified by chromatography and repeated recrystallization from hexane to give 17/3-acetoxy-4-androsteno [3.2-d]-2'-methylpyrimidine in the form of colorless prisms, M.P. 170.4-1 7,l.8 C. (corn), [a] :+143.4- (1% in chloroform); ultraviolet maxima. at 229, 256 and 302 m (E=11,700; 5,300 and 12,600).

Am zlysis.-Calcd. for C H N O' C, 75.75; H, 8.48; N, 7.36. Found: C, 75.60; H, 8.51; N, 7.43.

When measured by its eflect upon the growth of the levator' ani muscle in the rat, 175-alcetoxy-4-1androsteno [3.2-d] -2-methylpyrimidine was found to possess myotrophic activity.

17B hydroxy-4- drosteno[3.2-d] -2-methylpyrimidine (obtained as the initial reaction" product above prior to acetylation) can be reacted with propionic anhydride, caproyl chloride, succinic anhydride, [i-cyclopentylpropionyl chloride, benzoyl chloride, p-nitnobenzoyl chloride, 3,4,5 trimethoxybenzoyl chloride, phenylacetyl chloride, cinnamoyl chloride, p-chlorophenoxyacetyl chloride, or 5- cyclohexylpropionic anhydride, by heating in the presence of pyridine, to give, respectively, 17B-propionoxy-4-androsteno[3.2-d]-2' methylpyrimidine, 17,8-capr0yloxy-4- androsteno[3.2-'d] -2'-methylpyrimidine, 175 (fi-carboxypropionoxy) 4-androsteno[3.2-d]-2' methylpyrimidine; 17B (B-cyclopentylpropionoxy)-4- androsteno[3.2 d]-2- methylpyrimidine, 17p benzoyloxy-4- androstenot3.2-d]- 2' methylpyrimidine, 175 (p-nitrobenZoyloxy)-4 androsteno[3.2-d] 2-methylpyrimidine, :17/3-'(3,4,5-trimeth oxybenzoyl-oxy) 4 androsten 0[3.2-d]-2'methylpyrimidine, 17/3 phenylacetoxy-4-androsteno[3.2-d]-2methylpyrimidine, 17,3 cinnamoyloxy-4-androsteno[3.2-d]-2- methylpyrimidine, 17,8 4 chlorophenoxyacetoxy) 4- androsteno[3.2-d]-2'-methylpyrimidine, or 17fi-(fl-cyclohexylpropionoxy) 4-androsteno[3.2-d] -2-methylpyrimidine.

EXAMPLE 6 Sodium ethoxide solution (from 0.69 g. of sodium and 20 ml. of absolute ethanol) .was added to' a mixture of 6.32 g. of 2-hydroxymethylene-4-androsten-17fl-ol-3-or1e, 2.82 g. of acetamidine hydrochloride and 50 ml. of anhydrous ethanol. After one-half hour at room temperature, the mixture was heated to reflux for six hours. The basic fraction was isolated by the method described in Example 1, part (b) and the product purified by chromatography. The resulting 17B-hydroxy 4 androsteno- [3.2-d]-2'-methylpyrimidine was acetylated with acetic ,anhydride in pyridine to give a sample of .17 S-acetoxy-4- androsteno[3.2-d]-2'-me ylpyrimidine, M.P. 173-178 C. (uncorn), the same compound as obtained in ExampleS.

EXAMPLE 7 (a) 2-hydroxym et hylene 4 pregnene-17a,2l-di0l- 3,11,20-tri0ne-17,20;20,21 bismethylenedioxy derivative was prepared from 10.0 g. of 4-pregnene- 17a,21-di0l-3,11,

rivativeQWas prepared from 4.30 g. of Z-hydroxymethylene- 4-pregnene ;,21 diol -3,1l,20-trione 17,20;20,21-bismethylenedioxy derivative, 1.25 g. of tormamidine hydrochloride, 1.80 rnl. of triethylam-ine and 15 ml. of dimethylformamide. The mixture was refluxed for two and onev X is '0, Z is Oi-I, Y and Y' are CH "(17 hydroxy dihydroxy 11,20 dioxo-4-pregneno[3.2ad]pyrimidine 17,20;20,2l-bismethylenedioxy derivative, M.P. 283.0- 291.4 C. (corr.).

, Analysin- Cal'cd. for C H 3N 0 c, 68.47; H, 6.90;

N, 6.39. Found: C, 68.20; H, 7.08; N, 6.24. V The bismethylenedioxy grouping can be cleaved by treating the compound with perchloric acid in acetic acid solution to yield 1'7 11,21 dihydnoxy --11,20 dioxo-4-pregneno [3.2 d]pyrimidine [VI; R is H, R" is COCH O'H, R" is H,

EXAMPLE 8 J 7 0;,21 dihydroxy 11,20 dioxof- 4 pregn n0[3.2-d] 2' methylpyrimidine l7,20;20,21-bismethylenedi0xy derivative was prepared from 4.30 g. of 2hydroxymethylene- 4-pregnene 17a,21-diol-3,1 l,20-tri0ne l7,2l0;20,21-bisrhethylenedioxy derivative, 1.15v -g. of acetamidine hydrochloride, 1.73 ml. of .triethylamine and 10 ml. of dimethylf ormamide. The mixture was refluxed for one hour and worked up according to the manipulative procedure described above in Example 1, part (b). The product was recrystallized from an ethyl acetate hexane mixture and then several [times from methanl to give 17a,21-dihydroxy -1 1,20-dioxo-4-pregneno 3 .-2'-d] 2'-methylpyrirnidine 17,20;20,2labi-smethylenedioxy derivative, M.P. "217.2- 221.2 C. (com). A

AmalysiS.-Calcd. for C H N O C, 69.00; H, 7.13; N, 6.19. Found; C, 68.86; H, 7.13; N, 5.91.

a guru which/was converted to its sodium salt and used directly in the next reaction without further purification. I

(b) 175 hydroxy 17a ethyl 4 androsteno[3.2-d]- 2'-methylpyrimidine [VI; R is H, R is 'C H R" is CH X is H Z is CH, Y and Y are CH can .be prepared by causing Z-hydroxymethylene 17a ethyl-4-androsten- 17,8-01-3-one to react with acetamidine according to the manipulative procedure described above in Example 1,

part (b).

EXAMPLE 14 (a) 2 hydroxymethylene 17w vinyl 4 androsten- J7fi-0l-3-0net-Amixture of 12.04 g. of 17oc-VillYl-4-HH- drosten-17B-ol-3 0ne, 12 ml. of ethyl formate and 4.0 -g. of

sodium hydride in 300 of benzene was kept at room temperature for three days under a nitrogen atmosphere. After this time about 2 g. of sodium methoxide was added and the reaction mixture allowed to stand for seven days longer. The reaction mixture wasworked up according to the manipulative procedure described above in Example 4, part (a), giving. 11.46 g. of 2..hydroxymethylene-17uvinyl-4-andros-ten-17fi-ol-3-one in semi-crystalline form.

(5) 17,8 hydroxy 17a vinyl 4 andr0steno[3.2- d]-2'-methylpyrimidine [VI; R is H, R is CH=CH R" is CH X is H Z is OH, Y and Y are CH can be prepared by causing 2-hydroxymethylene-17a-vinyl-4-androsten-17B-ol-3-one to react with acetamidine according to the manipulative procedure described above in Example I 1, part (b).

The bismethy-lenedioxy grouping can be cleaved by treating the compound with perchloric acid in acetic acid solution to yield 17,21-di-l1YdcIOVY-1 1,20-dioxo-4-pregneno R" is CH3, X is o, z is OH, Y and Y are CH3].

' EXAMPLE 9 17,8 hydroxy 17oz methylandrostan0[3.2-zl] 2- ethylpyrimidine [V; R is H, R is CH R".is C H X is H ,Z is CH and Y and Y are CH can be prepared by preparedby replacement of the acetamidine hydrochloride in Example 1 by a molar equivalent amount of isobutyr amidine hydrochloride. 1

. prepared by replacement of the acetamidinehydrochloride in Example 1 by amolar equivalent amount of n-v-alermidine hydrochloride. a

' x EXAlVIPLE 12 I prepared by replacement of the acetamidine hydrochloride in Example'l by a molar equivalent amount of n-butyr-- amidine hydrochloride.

' EXAMPLE 13 of sodium hydride in 350ml. of benzene according to the manipulative procedure described; above in Example 4,

part (a) The acidic product was obtained in the form of 17a methylandrostan0[3.2-d] 2"- EXAMPLE 15 (a) 2 hydroxymethyleue 17oz m ethyletiocholan 17B-0l-3-0na-To 4.8 g. (0.2 mole) of sodium hydride 'suspended'in ml. of benzene was added 3.2. g. (0.1 mole) of methanol. After the reaction subsided, the mixturewas heated to boiling, cooled, and treated with a mixture of 2 0.8 g. (0.068 mole) of l7a-methyletiocho- Ian-1 7;8-ol-3-one, 75 ml. of benzene, and 21 ml. of ethyl formate; The mixture was stirred vigorously for four hours, mixed with 200 ml. of Water, and the layers were separated. The water layer was Washed with ether and then acidified with hydrochloric acid. The resulting pre-' cipitate was collected'by filtration and dried, giving 17:8 g. .of Z-hydroxymethylene-l7a-mcthyletiocholan-17,8-01- 3-one, suitable fame in the succeeding'reaction. A sample was further purified by chromatography on g. of silica gel in an equal. .Volume mixture of ether and pentane. 'The' resulting solid was recrystallized from ether, giving colorless needles, M.P. 205.6-2116 C.

(corn), [a] =+O.3iO.2, (1% in chloroform); ultraviolet maxima at 285 and 347 m '(E=7,200 and 1,500). Analysis.Calcd. for C H O C, 75.86; H, 9.70. Found: C, 75.69; H, 9.74. J

(b) 17,8 hydroxy 17a methyletiocholano[3.2-d]- 2'-methylpy rimidinc [V; R isH, R and R are CH X is H Z is OH, Y and Y are CH (rings A/B cis)] can be preparedby causing Z-hydroxyniethylehdl7amethyl- ,etiocholan 17B-ol-3-one to reactjwith acet'arnidine accord- .ing to themanipulative procedure described above in Example 1, part (11 7 EXAMPLE 16". g (a) 2 hydroxymethylene 17cc methyl J9 nonmdr0start-17fi-0l-3-One was prepared from 4.35 g. of

methyl-19norandrostan-17,8-ol-3-one [Bowers et al., J.

m. Chem, Soc. '79, 4555 1957)], 1 0; ml. of ethyl formate and 2.40 g. of sodium hydride according. to the ma- .nipulative procedure described above in Example 4, part (a). There wasthus obtained 4.35 g. of .Z-hydroxyniethylene 17damethyl l9-norandrostan-l7,6-ol 3 one, v70

190-200? C. (uncorr.). 1 (b) 170- hydroxy 17o: methyl 19 norandrostano [3.2-d]-2-methylpyrimidine [V; R is H, R and R" are.

icH gX is H Zji's OH, Y is H, Y is CH can beprepared by causing 2-hydroxyrnethylene l7u-methyl l9-norandlOStali-UfljOl-Iibllfl to react with acetamidine accordwith 500 ml. of hot of allopregnane-3,20-dione .ethyl formate, .sodium and 15 ml. of methanol) in 70 ml. of pyridine ing to the manipulative procedure described above in Ex- .ample 1, part (b).

7 EXAMPLE 17 (a) 17m ethyl 2 hydroxymethyleneandrostan-I7B- ol-3-0ne was prepared from 7.0 g. of 17a-ethylandrostan- 17/8-ol-3-one, 8 ml. of ethyl formate and 3.8 g. of sodium methoxide in 150 ml. of benzene according to the manipulative procedure described above in Example 1, part (a). The product was obtained in the form of the solid sodium salt and used directly in the next reaction.

, (b) 17,8 hydroxy 170a ethylandrstano[3.2-d]-2- methylpyrimidine [V; R is H, R is C H R" is CH X is H Z is OH, Y and Y are CH can be prepared by causing 17a ethyl Z-hyd'roxymethylene-androstan-17,8- ol-3-one to react with acetamidine according to the manipulative procedure described above in Example 1, part (b).

EXAMPLE 1'8 7 (a) A'llopregnan 3/8 ol 20 one ZO-ethylene glycol ketal-A mixture of 27.4 g. (0.086 mole) of allopregnan-3fi-ol-20-one, 33 ml. of ethylene glycol, 700 ml. of

benzene and 1 g. of p-toluenesulfonic acid was refluxed for 78 hours with a water separator in the system. The

reaction mixture was then cooled and shaken with 100 ml. of 2 N sodium hydroxide solution, and the resulting mixture was filtered to collect 20.5 g. of allopregnan-3flol-20-one ZO-ethylene glycol ketal, M.P. 16616-9 C. (uncorr.). When the latter was recrystallized from acetone, the compound was obtained in the form of colorless plates, M.P.' 172.5-175 C. (uncorr.).

(b) All0pregrmne-3,20-di0ne ZO-ethylene glycol ketal. Chromic oxide (26.6 g.) was added in small portions to 425 ml. of pyridine at -30 C. To this mixture was added all at once a solution of 19.5 g. (0.054 mole) of allopregnan-3B-ol-20-one 20-ethylene glycol ketal in 250 ml. of pyridine. The reaction mixture was stirred at room temperature for 18 hours, diluted with 1 liter of hot benzene and filtered. The filtered solid was washed benzene, and the combined filtrates were washed with four 500 ml. portions'of Water fol- .lowed by one 200 ml. portion of saturated sodium chloride solution.

in vacuo, and the residue was triturated with 50 ml. of

The organic solvent was then concentrated the mixture and concentration of the filtrate to a volume of 20 ml. gave a small additional amount of solid product. The combined solid product was recrystallized from ethylacetate using activated charcoal for decolorizing purposes to give 12.6 g. 20-ethylene glycol ketal in the form of blades and plates, M.P. 190191.5 C. (uncorr.).

(c) 2 hydroxymethyleneallopregnane -3,20-di0ne 20- ethylene glycol ketal was prepared from 2.45 g. of allopregnane-3,20-dione 20-ethylene glycol ketal, 20 m1. of and sodium methoxide. (from 0.33 g. of

methanol. Filtration of according to the manipulative procedure described below in Example 19, part (c). There was thus obtained 2.64 g. of 2 hydroxymethyleneallopregnans-3,ZO-dione 210- ethylene glycol ketal, used in the next reaction without .further purification.

(d) 20 0x0all0pregrtano[3.2-d] 2 methylpyrimidine [V; R is H, R is COCH R" is CH X isH Z is H, Y and Y are CH (rings A/B trans)] can be prepared by causing 20-ethylene glycol ketal to react with acetamidine ac- ..cording to the manipulative procedure described above in Example 1, part (b), followed by heating with dilute acetic acid to cleave theketal group.

' {EXAMPLE 19 ZO-ethyZene glycol ketal was prepared from g. of pregnan-3nt-ol-20-one, 30 g. of ethylene glycol, 0.9 g. of p-toluenesulfonic acid monohydrate and 700 ml. of benzene according to the manipula- 2-hydroxymethyleneallopregnane-3 ,20dione yet hyl formate.

'ZO-ethylene glycol ketal, suitable for conversion solution filtered.

,Foundr C, 76.13; H, 10.75.

(b) Pregnane-3,20-di0ne ZO-ethylene glycol ketal was prepared from 25.3 g. of pregnan-3q-ol-20-one 20-ethylene glycol ketal, 33 g.- of chromic oxide and 630 ml. of pyridine according to the manipulative procedure described above in Example 18, part (b).. The product was recrystallized from 400 ml. of methanol to give 17.5 g. of pregnane-3,20-dione ZO-ethylene glycol ketal in the form of colorless leaflets, M.P. 169.8172.8 C. (corn),

[a] =+32.O:tO.1 (1% in chloroform).

Analysis.Calcd. for C H O C, 76.62; H, 10.07. Found: C, 76.93; H, 10.08.

(c) Z-hydroxymethylenepregnane-3,20-di0ne ZO-ethylene glycol ketal-Sodium methoxide was prepared by dissolving 0.73 g. (0.03 mole) of sodium hydride in 30 ml. of methanol and removing the excess methanol at 100 C. in vacuo. To the sodium methoxide were added ,100 ml. of pyridine, 5 .45 g. (0.0151 mole) of pregnanc- 3,20-dione 20-ethylene glycol ketal and then 30 ml. of The reaction mixture was allowed to stand at room temperature for twenty-one hours and concentrated to dryness in vacuo below 45 C. The residue was dissolved in water, and carbon dioxide was passed into the solution until it reached a pH of 8. The precipitated product was collected by filtration and air dried, giving 5.9 g. of 2-hydroxymethylenepregnane-3,20-dione to the pyrimidine derivative. a

(51) 20 oxopregm'mo[3.2-d]-2'-methylpyrimidine [V; R is H, R is COCH ,'R is CH X is H Z is H, Y and Y are CH (rings A/B cis)] can be prepared by causing 2-hydroxymethylenepregnane-3,20-dione 20-ethylene glycol ketal. to react with acetarrridine according to the manipulative procedure described above in Example 1, part (b), followed by heating with .dilute acetic acid to cleave the ketal group.

Example 20 i a) 2- acetyl l7,8;acet0ryawdr0stah-3 0ne-A mixture 0f 9.6 g. (0. 16 mole) of glacialacetic acid and 50 ml. of ethylene dichloride was cooled in an ice-bath, and dry boron trifluoride gas was passed into the solution until it was saturated. With continued addition of boron trifluoride, a solution of 11.60 g. (0.04 mole) or" androstan-17 3-ol-3-one and 12.2 g. (11.4 ml., 0.12 mole) of acetic anhydride in ml. of ethylene dichloride was added. The reaction mixture was stirred in the ice-bath for thirty minutes and at room temperature for three hours, and then poured into a solution of 30 g. of sodium acetate trihydrate in 200 ml. of Water. vent was distilled ofLand the residue refluxed for forty- The organic solfive minutes and diluted with waterl 'The solid product was collected ,by fil-tnation, suspended in 200 ml. of methanol containing 23 ml. of 35% sodium hydroxide solution with stirring, 25ml. ofwater'was added,- and the solution allowed to stand for one hour. The solution was acidified lwith glacial acetic acid, the methanol rewas added tojcold, dilute "sulfuric acid and the product collected, washed, dissolved in hot methanol, and the 1 Water was added to the filtrate to the 1 point of turbidity, and the. product which separated upon 1 cooling was collected and dried at 70 vC.; yield 11.59 g., 1 MP. 132158 C. (uncorr.). The latter was dissolved in in ii-hexane and chromatographed on alumina. Thefrac tion eluted with 20% ether in n-pentane was recrystallized from acetone andfidried in vacuo at 110 C. for

eighthours, giving 6.98 g. of 24acetyl-17/3-acetoxyandro5 (1% in chloroform); ultraviolet maximum at 290 ma Analysis.-Calcd. i or C H O C, 73.76; H, 9.15. Found: C, 73.80; H, 9.55.

(b) Z-acetylqndrostan-J713-l-3 0ne.--A solution of 2- acetyl 17,8 acetoxyan-drost-an 3 one in methanol was treated with an. excess ot 35 sodium hydroxide solution, land'the mixture was allowed to stand at room temperature for 50116 hour. The reaction mixture wasneutra'lized with acetic acidian'd diluted with water, and the product was isolated and purifiedby chromatography on silica .gel, giving 2- acetylandrostan-17fi-ol-3 one, M.P. 149L6-154J0 C. (corn), [a] =+62;3:0.1 (1% in chloroform), when recrystallized from an ethyl acetatepetroleum ether mixture.

(0) 17,8 hydrOxyandr stdndiZ-d] 2",6' dimethyla pyrimidine [V; R is CH R is H, R" is CH X is H Z is OH, Yand Y are CH can be prepared by causing 2-acetylandrostan-17,B-ol3-one to re act with acetamidine according to the" manipulative procedure described above in Example 1, part (b).

Example 21 (a) 2-(n-butyryl)andr0stan-17p-ol-3-one was prepared from 2.7.68 g; of 17/3 (n butyryloxy)androstan-3aone t 1% in chloroform); lltraviolet maximumat .290 m,

( 7 V Analysis. CalC(l. for 0 1-15 03: C, 76.62; H; 10.07. Found: 0, 76.70; H, 10.19. a a

pared bycausing Z-(n-butyryDandroStan-17,8-ol-3-one to reactwith acetamidine according to the manipulative procedure described above in Example 1, part (b).

Example 22; (a) Z-hydroxyme'thylene 4,6 androstqdienJZQ-old- "one prepared from 12.41 g. of 4,6 .-androstadien-1'7-,B-

ol-3. -one, 14 of ethyl formate and 3.9 g. of sodium hydride according to the manipulative procedure described above-in Example4, part (a); :There was thus obtained Zis OH, Y and Y are CH canbe prepared by causing 2-hydroxymethy1ene-4,6 andr ostadien-17fi-ol-3-o-ne :to react with acetamidine according to the manipulative procedure described above in-Example 1, part (b). I

l 7 Example 2 3 i p 7 d]-2-methylpyrir tidine VI; R is H, 'R' is CECE, R" is' Cl-I X is H Z is CH, Y and Y are CH can be pre- .methyl lfi androstadien-17B ol3 0ne, 12.01 151. orfeu 1 tormate and gfiroi sodium hydri'de -in25 0 ml. of benizone according to the manipulative procedure described 5.3 g. of 2-hydroxymethylene-17a-methyl4,6-androsta =dienl7fi-ol-3 one, M.P. 117-123? C. (uncorn).

(b) l 7B-hydroxya17a-r nethyl 4,6 androstadinofiid]-2'-methy lpyrimidine [VII; R is H, R and R" are CH X is H Z is OH, Y and Y are CH can be prepared by causing Z-hyd-roxymethylene 17a methyl-4,6-androstadien-17fl ol-3-one to react with acetamidine according to the manipulative procedure described above in Example EXAMPLE 24 v (a) 2 Q hydroxymethyl ene 170: ethyl 4,6-androstadien-J 7 ,B-0l-3-0ne was preparedfrom 8.83 g. of 17a-ethy1- 4,6 androstadien-1'7p-ol-3-one, 10 m1. of ethyl formate and 2.8 g. of sodiumhydride in 200 ml; of benzene according to the manipulative procedure described above inExample 4, :part (a). There was thus obtained 9.68' g. of 2 hydroxymethylene 17a ethyl 4,6-androstadien-17/3- ol-3-one in the form of its sodium salt. l g (b) 17 hydroxy 17a ethyl 4,6 androstadieno- [3.2-d]-,2-methylpyridimidine [VIE R is H, R is C H R" is CH X is H Z is OH. Y and Y are CH can be prepared by causing 2-hydroxymethylene-17a ethyl-4,6- androstadien-17B-ol-3 one to react with acetamidine according to the manipulative procedure described above in Example 1, part (b).

EXAMPLE 2'5 tate.

EXAMPLE-2e (a) 170i ethynyl 2 hydrqxymethylene 4 androsten-17/8-0l-3-0na-T0 a solution of 14.2 g. of 17ot-ethynyl-4-androsten17B-ol-3-one in 300 m1, of dry pyridine was added'23" ml. of dry ethyl formate and then a solution of sodium ethoxide in ethanol from 2.1 g. or" sodium and 351111. of absolute ethanol). The reaction mixture was allowed to stand at room temperature for forty-two hours and then poured onto ice-water; Glacial acetic acid (218 ml.) was'a'dded andthe gummy product was separated and'dissolved in ether. The ether solution was washed with ajsolution of 30 g. of potassium hydroxide in 1.5 liters of water, and the aqueous layer was cooled to 5 C. and acidified with 6 N hydrochloric acid. The precipitated product was collected by filtration and dried in vacuo over phosphorus pentoxide at 60 .C.,'giving 13.5 g. of 1704- ethynyl-2rhydroxymethylene-4-androsten-17j3-ol-3qone.

pared by causing'.1 7a-ethynyl-2-hydroxymethylene-4-androsten 17fl-ol-3-one to react with acetamidine according to the manipulative procedure described above in Exam- 'pl 1.1mm) t p EXAMPLE 27' (a)... 2 hydroxymethylene 4 pfegnen 20 3 ol- 3-0ne was prepared;from 4;97tg. of 4pregnen-20B-ol-3-one, 5

ml. of ethyl formate and 1.0 g. of sodium hydride in described above" in Example l. part (a).

. ml. of benzene according to thenianipulative procedure causing" Z hydroxymethylene-45pregnen-2OB-olfB one tore- I I actwith acetamidine accordingtof'the manipulative pro 1 5 EXAMPLE 2:;

20 x0 4 pregneno[3.2-d]-2-methylpyrimidine [VI; R is H, R is COCH R is CH X is H Z is H}, Y and Y are CH can be prepared by treating a solution of 205'- hydroxy-4-pregneno[3.2-d]-2-methylpyrimidine in glacial acetic acid with a solution of chromic oxidein aqueous acetic acid.

EXAMPLE 29 (a) 2 hydroxymethylene 4,4,17a trimethyl 5 androsten-Ufl-ol-fi-one Was prepared from 6.2 g. of 4,4, 17oc-trimethyl-5-androsten-l7B-ol-3-one, 16 ml. of ethyl formate and sodium methoxide (from 2.2 g. of sodium and 40 ml. of methanol) in 400 ml. of benzene according to the manipulative procedure described above in Example 1, part (a). There was thus obtained 5.54 g. of 2-hydroxymethylene-4,4,17a-trimethyl-S-androsten-17fi-ol-3-one.

(b) 17,8 hydroxy 4,4,17a trimethyl 5 androsteno- [3.2-d]-2-methylpyrimidine can be prepared by causing 2 hydroxymethylene 4,4,17a-trimethyl-5-androsten-17-fi ol-3-one to react with acetamidine according to the manipulative procedure described above in Example 1, part (b).

EXAMPLE 30 (a) 2 hydroxymethyler ze 4,4 dimethyl 5 androsten-17fl-0l-3-0ne was prepared from 6.69 g. of 4,4 -di methyl-S-androsten-1-7B-ol-3-one, 9.5 ml. of ethyl formate, 0.95 g. of sodium and 18-20 ml. ofethanol in 65 ml. of pyridine according to the manipulative procedure described above in Example 26, part (a). There was thus obtained 5.21 g. of 2-hydroxymethylene-4,4-dimethyl-5-androsten- 17fi1-ol-3-one.v

(b) 4,4 dimethyl 175 hydroxy 5 androsteno [3.2- d] -2-methylpyrimidine can be prepared'by causing 2-hydroxymethylene-4,4-dimethyl-5-androsten-17fi-o1-3-one to react with acetamidine according to the manipulative pro cedure described above in Example 1, part (b).

EXAMPLE 31 EXAMPLE 32 (a) 2 hydroxymethylene 60 170; dimethyl-4-andr0- sten-17fi-0l-3-0ne was prepared from 5.0 g. of 6a,l7oc-dimethyl-4-androsten-l7 fi-ol-3-one, 5 .0 m1, of ethyl formate and 1.5 g. of sodium hydride in 100 ml. of benzene ac: cording to the manipulative proceduredescribed above in Example 4, part (a). i i i (b) 6a,17cc dimethyl 1713 hydroxy 4 a ndrosteno [3 .2-d] -2'-methylpyrimidine can be prepared by causing 2 hydroxymethylene 60:,17 a dimethyl-4-androsten-17 3- o1-3-one to react with acetamidine according to the manipulative procedure described above in Example 1, part (b') EXAMPLE 33 (a) 2 hydroxymethylene 4- pregnene 170:,21 --di o l- 3,11,20-trione was prepared from 2.0 g. (0.005 mole)v of 2l-acetoxy 4-pregnen l7o o1 3,11,20 trione (cortisone acetate) and 1.0 g.of sodium hydride in-100 ml. of pyridine according to the manipulative procedure described above in Example 26,v part .(a), all operations being carried out, in a nitrogen atmosphere. In the process the 21-acetoxy group was saponified to give 1.3 g'.

EXAMPLE 34 (a '2 hydroxymethylene 17a ethynylandrostan- I 17B-ol-0ne was prepared from 7.54 g. of 17a-ethynylandrostan-l7fiaol-one, 11.5 ml. of ethyl formate and sodimethoxide (from 1.10 g. of sodium and 20 ml. of methanol) in 250 ml. of pyridine according to the manipulative. procedure described above in Example 26, part (a).

The crude producLhad a melting point of 171-177.5 C. (uncorr.).

(b) 1711- hydroxy 17a ethynylandr0smn0[3.2 d]- 2-methylpyrimidine '[V, R is H, R is CECH, R" is CH X is H Z-is OH, Y and Y are CH can be prepared by causing 2-hydroxymethylene-17a-ethynylandrostan- 17B-ol-3-one to react with acetamidine according to the manipulative procedure, described above in Example 1, part (b).

EXAMPLE 35 EXAMPLE 36 (a) 2 hydroxymethylene 4 pregnene 20,21 dz'ol- 3-one can be prepared by replacement of the Not-methyl- 4-androsten-17-B-ol-3-one in Example. 4, part (a) by a 'molar equivalent amount of 4-pregnene20,2l-diol-3-one.

(b)-20,2-1 7 dihydroxy 4 pregne no[3.2 d] 2- methylpyrimia'i ne [VI; R is H, R is CH(OH)CH OH, R is CH X is H Z is H, Y and Y are CH can be prepared by causing, Z-hydroxymethylene-4-pregnene-20, 21-diol-3-one to react with acetamidine according to the manipulative procedure described above in Example 1, part (b);

EXAMPLE 37 (a) 2 hydroxymethylene 9 fluoro 4 pregnene- *11,8,17a,21-tri0l-3,20-di0ne 20-monoethylene glycol ketal can be prepared by replacement of the 17u-methyl-4- androsten-17B-ol-3-oneinExample 4, part (a) by a molar equivalent amount p} of 9-fluoro-4-pregnene-1lfi,l7a,2l- 'triol-3,20-dione 20-mono'ethylene glycol ketal.

(b) 9 fluoro '11B,17ot,21 trihydroxy 20 0x0 4- 'pieghenoBJ-d] -2--methylpyrimidine can be prepared by causing. Z-hydroxymethylene-9-fiuor0-4-pregnene-1 lfl, 17 a, 21-triol-3,20-dione 20-monoethylene glycol ketal to react with acetamidine according to the manipulative procedure 'describedabove'in Example 1, part (19), followed by heating with dilute acetic acid to cleave the ketal group.

. .V X E i (a) :2 -,hydroxym ethylen i 4 p regnena- 16a,17a,21-

triol 3,20. di0n-9;8,11Boxide v 20-manoethylene glycol ketal canbe p'reparedby replacement of the 17a-methyl- 4-androsten-17B-ol3-one in Example 4, part (a) by a ample 1, part (b).

. 17 molar equivalent amount of 4-pr'egnene-16a,17a,2l-triol- 3,2 -,dion e-9/3,ll 3-oxide 16a,21 -diacetate 20-monoethylene glycol ketal.

(b) '16,1 7a,21 trz'hydroxy 20 oxo 9 3,113 oxida- 4-pregneno[3.2-d]-2'-methylpyrimidine can be prepared by causing 2-hydroxymethylene-4 pregnene-16d,17bc,21- triol-'3,20-dione-9B,1lfl oxide ZO-monoethylene glycol to react with'acetamidine according tothe manipulative procedure described above in Example 1, part (b), followed by heating with dilute acetic acid to cleave the ketal group. i

EXAMPLE 39 (a) 2 formyl 1,4 pregnadz'ene 1711,21 diol 3,11,

. 20-tri0ne 20-m0rtoethylene glycol ketal can be prepared by replacement of the '17a-methyl-4-androsten-175-01-3- -one in Example 4,part (a) by a molar equivalent amount of 1,4-pregnadiene-l721,21-di0l-3,11,20-trione 20-monoethylene glycol ketal.

(b) 1705,21 dihydroxy 11,20 dioxo (1,3)5 pregnbtrienoIBZ-d]-2 methylpyrimidine can" be prepared by causing 2-formyl-1,4-pregnadiene-l7a,21-diol-3,1 1,20-trione 20-monoethylene glycol ketal to react with acetamidine according to the manipulative procedure described above in Example 1, part (b), followed by heating with dilute acetic acid to cleave the ketal group.

EXAMPLE 40' (a) 2- hydroxymethylene 7oz propynyl 6 methyl- 4-androsten-17fi-ol-3-one can be prepared by replacement of the 17a-methyl-4-androsten-17,6-01-3-one in Example 4,

part (a) by a molar equivalent amount of 17u-propynyl- 6-methyl-4-androsten-17,8-ol-3-one. '(b) 17,8 hydroxy 17a propynyl 6 methyl -"4- androsteno[3.2-d]-2-methylpyrimidine can be prepared :by causing Z-hydroxymethylene-l7a-propynyl-6-methyl-4- vandrosten-l7 8aol-3-one'to react with acetamidine according to the manipulative procedure described above in Ex- EXAMPLE 41 (a) 2 hydroxymethylene 17oz methyl 4 androsten-17fi-ol-3 one in theform of the copper chelate (2.07

'g.,.M.P. 20'5220 C.) was brominated with 1.46 g. of

bromine in 100 ml. of carbon tetrachloride to give 2- -bromo 2 hydroxymethylene 17a methyl -4 andros- :-tenl'7fi-ol-3-one. The latter can be dehydrobrominated by heating with collidine to give 2-formyl-17a-methyl-L4- --androstadien-17B-ol-3 one.

(b) 17/3 hydroxy 17oz -tmethyl (1,3)5-androstatri eno[3.2-d] -2'-methylpyrimidinecan be prepared by causing 2-formyl-l7a-methyl-1,4-androstadien-17p-ol-3-one to react with acetamidine according to themanipulative pro- 7 c'edure described abovein Example 1, part (b).

. EXAMPLE 42 v (a) Z-hydroxymethylene-4-pregneneJ 1 3,1 7a,21 triol- 3,20-dione 20-monoethylene glycol ketal can be prepared by replacement of the 1 7a-methyl-4-androsten-17,6-01-3- one in Example 4, part (a) by a molar equivalent amount '-of; 2l-acetoxy:4'-.pregnene-llfi,17u diol -'3,20 dione 20- monoethylene glycol ketal. ('hydrocortisone acetate 20- monoethylene glycol ketal).

(b) 11,8,1704,21-trihydr0xy-20-0xo-4 pregneno[3.2-d]- 2-methylpyrimidin e [VI; R is H R is COCH OH, R" is CH X is (H) (OH), 2 is OH, Y and Y are CH can be prepared by causing 2-hydroxymethylene-4-pregnene-ll5,l7u,21-triol-320-dione 20-morioethylene gly col ketal to react with acetamid'ine according to the manipulative procedure described above in Example 1, part (b), followed by heating .withdilute acetic acid to cleave the ketal group. b

1 EXAMPLE 43 R" is CH X is 0,

'be prepared by causing 2-hydroxymethylene-4,6-preg- 1O (a) 2l-hydroxymethylen e-46 pregnadiene 17a,21-di0l '3,1],20-trioneZO-monoethylene glycol ketal can be prepared by replacement of the l 7a-methyl-4-androstenfl7 3- 1S ol-3-one in Example 4, part (a) by a molar equivalent amount of 21-acetoxy-4,6-pregnadien-l7a-ol-3,11,20-tri- 'one 20-monoethylene glycol ketal.

(b) 17,21-dihya'roxy-1L20 dioxo 4,6 pregnadieno- [3.2-d]-2-mcthylpyrimidine [VII; R is H, R is COCH OH V Z is OH, Y and Y are CH can nadiene-l7a,2l-diol-3,l1,20-trione 20-rnonoethylene glycol ketal to react with acetarnidine according to the ma-' nipulative procedure described above in Example 1, part (b), followed by heating with dilute acetic acid to'cleave the ketal group.

EXAMPLE 44 a) Z-hydroxymethylene-4-pregnene-J 7 04-21 -diol 3,20-

dione 20-monoethylene glycol ketal can be prepared by replacement of the l7ot-methyl-4-androsten-17fi-ol-3-one' EXAMPLE 45 b (a) 2-hydroxymeflzylene-6-methyl-4-pregi2ene ;,21-

. di0l-3,11,20-lrione ZO-mmwethylene glycol ketal can be prepared by replacement of the 17a-methyl-4-androsten- 17p-ol-3-one in Example 4, part (a) by a molar equivalent amount of 2l-acetoxy-6-rnethyl-4-pregnen-l7cx-ol- 3,11,20-trione 20-monoethylene glycol ketal.

(b) 170:, ZJ-dihydroxy-J1,20-di0x0-6-methyl 4 pregnen0[3.2-d] -2'-methylpyrimidinc can be prepared by caus ing 2 -hydroxymethylene-6-methyl-4-pregnene-17a,21-diol- 3,11,20-trione 20-monoethylene glycol ketal to react with acetamidine according to the manipulative procedure described above in Example 1, part (b), followed by heating with dilute acetic acid to cleave the ketal group.

EXAMPLE 46 (a) Z-hydroxymethylene-9-flu0ro-6-methyl-4-pregnene- I70,21-di0l-3,]1,Z0-2ri0ne 20-mon0ethylene glycol ketal can be prepared by replacement of the l7wmethyl-4- androsten-17fl-ol 3-one in Example 4, part (a) by a molar equivalent amount of 21-acetoxy-9-fluoro-6-methyl-4- pregnen-17ol-ol-3,11,20-trione 20 monoethylene' glycol ketal.

(b) 17u,21-dihydr0xy-11,20-di0xo-9-flu0ro-6-methyl-4- pregr 2e1z0[3.2-d]-2'-mcthylpyrimidine can be prepared by causing 2-hydroxymethylene-9-fiuoro 6 methyl-4-pregnene-17a- 21-diol-3,l1,20-trione ZO-monoethylene glycol ketal to react with acetamidine according to the manipulative procedure described above in Example 1, part (b), followed by heating with dilute acetic acid to cleave the ketal group. a

EXAMPLE 47 (a) Z-hydroxymethylene-4-pregnene 1153160 170121- 7 tetrol-3,20-di0ne 20-monoethylene glycol ketal can be prepared by replacement of the l7a-methyl-4 androsten-17,8- ol-3-one in Example 4, part (a) by a molar equivalent amount of 2-1-acetoxy-4-pregnene-1 l fi,l6a,17a-triol-3,20-

dione 20-monoethylene glycol ketal.

(b) 11fi,-I6a,1711,21-tetrahydroxy-20-oxo 4 pregneno- [3.2-d]-2'-methylpyrimidine can beprepared by causing 2-hydroxymethylene-4 pregnene 11fl,l60c,170c,21-tetr01- 3,20-dione ZO-monoethylene glycol ketal 'to react with .acetamidine according to the manipulative procedure described above in Example 1, part (b'), followed by'heating with dilute acetic acid to cleave the ketal group.

v r EXAMPLE 48 i (a) 2-hydroxymethylene 4 pregnene-16u,17a,21-tri0l- 3,11,20-trine -m0n0ethylene glycol ketal can be prepared by replacement of the 17a-methyl-4-androsten-17flol-3one in Example 4, part (a) by a molar equivalent amount of 21-acetoxy-4-pregnene-16a,17a diol 3,11,20- trione 20-monoethylene glycol ketal.

(b) 16a,1 7a,21-trihydroxy-1 1,20-di0x0-4-pregneno [3 .2-

d]-2'r-mezhylpyrimidine can be prepared by causing 2-hydroxymethylene-4-pregnene-16a,l7a,21-triol 3,11,20-trione 20-monoethylene glycol ketal to react with acetamidineaccording to the manipulative procedure described above in Example 1, part' (b), followed by heating with dilute acetic acid to cleave the ketal group.

EXAMPLE 49 (a) 2-hydroxymethylene-4,17(20)-pregnadiene-11,B,21- di0l-3-0ne can be prepared by replacement of the 170:- methyl-4-androsten-17,8-ol-3-one in Example 4, part (a) by a molar equivalent amount of 4,l7(20)-pregnadiene- 115,21-diol-3-one.

(b) 11,6,21-dihydroxy-4J 7(20)-pregnadieno[3.2-d] -2'- methylpyrimidine can be prepared by causing 2-hydroxymethylene-4,17(20)-pregnadiene-115,21-diol-3-one to react with acetamidine according to the manipulative procedure described above in Example 1, part (b).

EXAMPLE 50 11p,17a,21-trihydr0xy-20 0x0 4 pregneno [3;2-d] -2- methylpyrimidine can be caused to react with p-toluenesulfonyl chloride in pyridine under mild conditions to give 2l-tosyloxy-1lB,17a-dihydroxy-20-oxo 4 pregneno[3.2- d]-2'-methylpyrimidine. The latter can be caused to re act with sodium bromide, sodium iodide, sodium chloride or sodium thiocyanate to give, respectively, 21-bromo, 21- iodo, 21-chloro or 21-thiocyano derivatives of 115,170:-

dihydroxy-ZO-oxo-4-pregneno[ 3 .2-d] -2'-methylpyrimidine.

EXAMPLE 5 1 (a) Z-hydroxymethyleneandrostane-6BJ7fl-di0l 3 one can be prepared by replacement of the 17a-methyl-4- androsten-17B-ol-3-one in Example 4, part (a) by a molar equivalent amount of androstane-6B,17,8-diol-3-one.

(b) 613,17fl-e ihydroxyandrostano[3.2-d] -2'-methylpy rimidine can be prepared by causing Z-hydroxymethyleneandrostane-G-fi,l7;8-di0l-3-one to react with acetamidine according to the manipulative procedure described above in Example 1, part (b).

EXAMPLE 52 (a) Z-hydroxymethylene-I 7a-ethynyl-4-androsten-17f?- 0l-3,11-di0ne can be prepared by replacement of the 170:- methyl-4-androsten-17fl-o1-3-one in Example 4, part (a) .by a molar equivalent amount of 17a-ethynyl-4-androsten- (b) 170: ethynyl 17B hydroxy 11 0x0 4 androsteno[3.2-d]-2-methylpyrimidine [VI; R is H, R is CECH, R" is CH X is 0, Z is OH, Y andY' are CH can be prepared by causing Z-hydroxymethylene-lhethynyl-4-androsten-17 9-01-3,1l-dione to react with acetamidine according to the manipulative procedure described above in Example 1, part (b).

. EXAMPLE 53 (a) 2 hydroxymethylene-17a methyl 4 androsten- 1 713-0l-3,11-dione can be prepared by replacement of the l7a-methyl-4-androsten-l7fl-ol-3-one in Example 4, part (a) by a molar equivalent amount of 17 -methyl-4-androsten- 17 5-01-3 1 l-dione.

(b) 175 methyl 17,8 hydroxy -11 0x0 4 andr0steno[3.2-d] -2'-methylpyrimidine [VI; R is H, R and R" are CH X is 0, Z is OH, Y and Y are CH can be prepared by causing 2-hydroxymethylene-17a-methyl-4- 'androsten-17fi-ol-3,1l-dione to react with acetamidine according to the manipulative procedure described above in Example 1, part (b). A

'20 EXAMPLE 54; t-

tive procedure described above in Example 1, part (b).

' EXAMPLE s5.

(a) 2' hydroxymethylene- 4 -,ai1drostene 65,17,8- di0l-3a0ne can be prepared by replacement of the 17ermethyl-4-androsten-17B-ol-3-one in Example 4, part (a) by a molar equivalent amount of 4-androstene-6fl, l7fldiol-3-one.

(b) 65,1713 dihytiroxy 4 androsteno [3.2-d]-2.-

nzethylpyrimidim can be prepared by causing 2-hydroxymethylene-4-androstene6fi,17fl-diol-3-one to react with acetamidine according to the manipulative procedure described'above in Example 1, part (b).

EXAMPLE 56 a (a) 2 hydroxymethylene 17a methyl 4 an- -drbstene 6],17/8-di0l-3-0ne can be prepared by replacement of the 17a-methyl-4-androsten-1'7fi-ol-3-one in Example 4, part (a) by a molar equivalent amount of 170cmethyl-4-androstene-6B,17/3-diol-3-one. r

(b) 17a methyl 6 3,175 dihydroxy 4 androsteno [3.2-d]-2-methylpyrimidine can be prepared by causing 2 -hydroxymethylene 17a methyl 4 androstene 65,

I 17 fl-diol-3-one to react with. acetamidine according to the -manipulative procedure described above inExample 1,

part (b).

EXAMPLE 57 V (a) 2 hydroxymethylene 4 androstene :,17/3- -di0l-30ne can beprepared by' replacement 'of the methyl-4-androsten-17fi-o1-3-one in Example 4, part (a) by a molar equivalent amount of 4-androstene-14a,1718- dio1-3-one.

(b) 14a,17;8 dz'hydroxy 4 andr0sten0[3.2-d] -2- methylpyfimidine can be prepared by causing 2-hydroxymethylene-4-androstene-14a,17 8-diol-3-one to react with acetamidine according to the manipulative procedure de- 'scribed' above in Example 1, part (b). v 50 e EXAMPLE 5:; i

(a) 2 -hydr0xymethylene 16f methyl 4 androsten-17p-ol-3-one can be prepared byrreplacement of the 17a-methyl-4-androsten-17fi-o1-3-one in Example 4, part (a) by a molar equivalent amount of l6 3-methyl-4- androsten-17fi-ol-3-one.

(b) 16,8 methyl 1713 hydroxy 4 androsteno [3.2-d]-2-methylpyrimidine can be prepared by causing 2 hydroxymethylene 16B methyl 4 -androsten 17pol-3-one to react with acetamidine according to the manipulative procedure described above in Example 1, part EXAMPLE 5 9 A (a) 2 hydroxymethylene 4 androstene -"11a,17;8- diol-3-0ne can be prepared by replacement of the 17ozimethyl-4-androsten-175-ol-3-one in Example 4, part (a) by a molar equivalent amount of 4-androstene-11a,175- diol-3-one.

' '(b) 11am -'dihydroxy 4 andr0sten0[3.2-d]-2'- methylpyrimidihe [VI; R and R are H, R". is CH X is (H) (OH), Z is OH, Y and Y' are CH 'can be prepared by causing 2-hydrOxYmethylene-4-androstene-1101,175- diol-S-one to react with acetamidine according to the manipulative procedure described above in Example 1, part 21 EXAMPLE 60 (a) 2 -hydroxymethylene 19 a nor 4 androstehe- 6,8,J7 3-diol-3-one can be prepared by replacement of the 17oc-methyl-4-androsten-17B-ol 3-one in Example 4, part (a) by a molar equivalent amount of 19-nor-4-androstene- 6/3,17 8-diol-3-one. a g

- (b) 65,175 dz'hydroxy 19 nor 4 -andrsteno '[3.2-a']-2-methylpyrimidine can be prepared by causing 2 -hydroxymethylene 19 nor 4 androstene 66,17,6- diol-3-one to react with acetamidine according to the manipulative procedure described above in Example 1, part (b).

EXAMPLE 61 EXAMPLE 62 (a) Z-hydroxymethylene-4-methyl-4 androsten' 17B- ol-3-0ne can be prepared by replacement of the 17stmethyl-4-androsten-l7fi-ol-3-one in Example 4, part (a) by a molar equivalent amount of 4-methyl-4-androsten- 17fi-ol-3-one.

I (b) 4 methyl 17f? hydroxy 4 andr0sten0[3.2-d]- A 2'-methylpyrimidine can be prepared by causing'Z-hydroxymethylene-4-methyl-4-androsten-17,8-ol-3-one to react With acetamidine according to the manipulative procedure described above in Example 1, part (b).

EXAMPLE 63 (a) 2 hydroxymethylene 4,1 7a dimethyl 4 andr0sfen-17B-0l-3-0ne can be prepared by replacement of the l7e -methyl-4-androsten-17,8-01-3-one in Example 4, part (a) by a molar equivalent amount of 4,17 a-dirnethyl- 4-androsten-17fl ol-3-one.

(b) 4,17ot dimethyl 17,8 hydroxy 4 androsten0['3.2-d] 2 methylpyrimidine can be prepared by causingZ hydroxymethylene- 4,17 dimethyl 4 an- ,drosten-17B-o1-3'one to react with acetamidine according to the manipulative procedure Example 1, part ([2).

described above in 7 EXAMPLE 64 l (a) 2 hydroxymethylene 17oz ethynyl 4,6 4 androstadien-J7/3-0l-3-ane can be prepared by replacement of the 17a-methyl-4-androsten-l7/3-ol-3-one in Example 4, part (a) by a molar e 4,6-androstadien-17fl-ol-3-one.

quivalent amount of 17oc-ethynyl- (b) 170a ethynyl 17B lzydroxy 4,6 andrbstadieno R is CH X is H Z is OH, Y and Y are CH can be prepared by causing 2-hydroxymethylene17a-ethynyl- 4,6-androstadien-17,8-01-3-one to react with acetamidine j accordingto the manipulative procedure described above in Example 1, part (b).

EXAMPLE 65 a (a) 2 hydroxymethyleneallopregnane 6B,17a,21- trial-3,20-dione 20-m0n0ethylene glycol ketal can be prepared by replacement of the 17ot-methyl-4-androsten- 17/8-ol-3-one in Example 4, part (a) by a molar equivalent amount of allopregnane-6/3,l7a,21-trio1-3,20-dione 20-rnonoethylene glycol ketal.

acetamidine according to the manipulative procedure described above in Example 1, part (h), followed by heating 7 with dilute hydrochloric acid to cleave the ketal group.

, EXAMPLE 66 (a) z hydroxymethylehe 4 pregnne 12 ,1'7a,21-

tri0l-3,20-di0ne 20-m0n0ethylene glycol ketal can be prepared by replacement of the .17pc-methyl-4-androsten- 17B-0l-3-one in Example 4, part (a) by a molar equivalent amount of 21-acet0xy-4-pregnene-12m,17a-diol-3,20-

dione 20- monoethylene glycol ketal. I p

(b) 1206,17OL,21 'trihydroxy 20 0x0 4 pregneno- [3.2-d]-2'-methylpyrimidine can be prepared by causing 2 hydroxymethylene 4 pregnene 12a,17u,21 triol- 3,20-di'o'ne 20-monoethylene glycol ketal to react with acetamidine according to the manipulativeprocedure described above in Example 1, part (5), followed by heating with dilute acetic acid to cleave the ketal group.

, EXAMPLE 67 V (a) 2 hydroxymethyleneallopregnane 1701,21 diol- 3,12,20-tri0ne 20-m0noethylene glycol ketal can be prepared by replacement of the l7a-methyl-4-androsten- 17B-ol-3-one in Example 4, part (a) by a molar equivalent amount of 2l-acetoxyallopregnamNovel-3,12,20-

trione ZO-monoethylene glycol ketal (b) 1704,21' dihydroxy 12,20 dioxoallopregnano- [3.2-d]-2'-methylpyrimidine can be prepared by causing 2 hydroxymethylallopregnane 17oc,21 diol 3,12,20- trione 20-monoethylene glycol ketal to react with acetamidine according to the manipulative procedure described above in Example 1, part (b), followed by heating with dilute acetic acid to cleave the ketal group.

EXAMPLE 68 (a) 2 hydroxymethylene 4,11 pregnadiene -3,2 0- 'dione 2 0-m0n0ethylene glycol ketal can be prepared by replacement of the 17a-methyl-4-androsten-17fl-ol-3-one in Example 4, part (a) by a molar equivalent amount of V 4,11-pregnadiene-3,20 dione ketal.

(b) 20 0x0 4,11 pregrtadienoHJ-d]-2'-methylpyrimidine can be prepared by causing 2-hydroxymethyl 20 monoethylene i glycol cue-4,11-pregnadiene-3,20dione 20-monoetbylene glycol ketal to react with 'acetamidine according to the manipulative procedure described above in Example 1, part (b),

followed by heating with dilute aceticacid to cleave. the

ketal group.

EXAMPLE 69 I (a) 2 hydroxymethylene 4 pregnen 17oz ol- 3,20-dione 20-m0n0ethylene glycol ketal can be prepared by replacement of the l'la-methyl-4-androsten-17,6-01-3- one in Example 4, part (a) by a molar equivalent amount of 4-pregnen-17a-ol-3,20-dione 20-monoethylene glycol ketal.

(b) hydroxy 20 0x0 4 pregneno[3.2-d]-2 methylpyrimidine [VI; R is H, R is COCH R" is CH X is H Z is OH, 'Y and Y are CH can be prepared by causing 2-hydroxymethylene-4-pregnen-1f7a-o1-3,20-dione 20-monoethylene glycol 'ketal to react with acetamid'ine according to the manipulative procedure described above in Example 1, part (b), followed .by heating with dilute acetic acid to cleave the ketal group. p I i w EXAMPLE 70 (a) 2 hydroxymethylene 17a. methyl 4 pregnene- 3,20-di0ne 20-m0n0ethylene glycol ketal canbe prepared by replacement of the -17at-methyl-4-androsten l718-01-3- one in Example .4, part (a) by a molar equivalent amount of 17a-methyl-4-pregnene-3,20-dione 20-monoethylene glycol ketal.

(b) 6fl,17a,21 trihydroxy -20 oxoa llopregnano- [3.2-d]-2'-methylpyrimidine can be prepared. by causing 2 hydroxymethyleneallopregnane 6,8,170i,21 triol 3,20-dione 20-monoethylene glycol ketal to react With (b) 1704 methyl 20 0x0 4 pregnen0[3.2-d-] 2'- methylpyrimidine can be prepared by causing 2-hydroxymethylene-17a-methyl-4-pregnene-3,20-dione 20 monoethylene glycol ketal to react with acetamidine according to the'manipulative procedure described in Example 1, part (12), followed by heating with dilute acetic acid to .cleave the ketal group.

EXAMPLE 71 (a) 2 hydroxymethylene 4 pregnen 65 ol 3,20- dionaZO-monoethylene glycol ketal can be prepared by .replacement 'of the 17oz methyl 4 androsten 1713-01- 3-one in Example 4, part (a) by a molar equivalent amount of 4-prgnen-6fi-ol-3,20-dione ZO-monoethylene glycol ketal.

methylpyrimidine can be prepared by causing 2-hydroxy- ,methylene-4-pregnen-6,B-ol-3,20-dione 20 monoethylene glycol ketal to reactrwith acetamidine according to the manipulative procedure described above in Example 1, part (b), followed by heating with dilute acetic acid to cleave the ketal group.

EXAMPLE 72 (a) 2 hydroxymethylene 4 pregnene 7fl,11,8 diol- 3,20-dione ZO-monoethylene glycol ketal can be prepared ,by replacement of the l7a-methyl-4 -androsten-l7/3-ol-3- ,one in Example 4, part (a) by a molar equivalent amount of 4-pregnene-7fi,11,8-diol-3,20-dione 2O monoethylene glycol ketal.

(b) 7,8,11/3-dihydroxy-20-0xo 4 pregneno [3.2-d]-2'- .methylpyrimidine can be prepared by causing Z-hydroxymethylene-4-pregnene-7fl,ll,8 diol 3,20 dione 20-monoethylene glycol ketal to react with acetamidine according vto the manipulative procedure described above in Example 1, part (b), followed by heating with dilute acetic acid to cleave the ketal group.

EXAMPLE 73 (a) Z-hydroxymethylene 12oz chlor-4-pregnene-17a, 21-di0l-3,11,20-tri0ne 20-m0n0ethylene glycol ketal can be prepared by preplacement of the l7a-methyl-4-andr0- sten-17fl-ol-3-one in Example 4, part (a) by a molar equivalent amount of 12a-chloro-4-pregnene-17a,2l-diol- 3,11,20-trione 20-monoethylene glycol ketal.

- (b) 120(- chloro-J70;,21-dihydr0xy-11,20-di0xo-4-pregneno[3.2-d]-2'-methylpyrimidine can be I prepared by causing 2 -hydroxymethylene-12a-chloro-4-pregnene-17a,

-21-diol-3,11,20-trione 20-monoethylene glycol ketal to .react with acetamidine according to the manipulative procedure described above in Example 1, part (b), followed by heating with dilute acetic acid to cleave the ketal i EXAMPLE 74 (a) Z-hydroxymethylene-l8,19-bisnor-4-pregncite-3,20- dione 20-m0n0ethylene glycol ketal can be prepared by replacement of the 17a-methyl-4-androsten-17fl-ol-3-one in Example 4, part (a) by a molar equivalent amount of 18,19-bisnor-4-pregnene-3,20-dione 20-monoethylene glycol ketal.

(b) 20 oxo-I8,19-bisnor-4-pregneno[3.2-]-2'-methylpyrimidine [VI; R is H, R is COCH R" is CH X is H Z is H, Y and Y are H] can be prepared by causing 2 hydroxymethylene 18,19 bisnor 4 pregnene 3,20- dione ZO-monoethylene glycol ketal to react with acetamidine according to the manipulative procedure described above in Example 1, part (b), followed by heating with dilute acetic acid to cleave the ketal group.

EXAMPLE 75 (a) 2 hydr0xymethylene-4-br0mo-4-pregnene-17a,2ldial-3,11,20-tri0n' 20-m0noethylene glycol ketal can be prepared by replacement of the l7a-methyl-4-androsten- 17fi-ol-3-one in Example 4, part (a) by a molar equivalent amount of 21-acetoxy-4-bromo-4-pregnen-17o -ol-3,

511,20-trione ZO-rnondethylene glycol ketal.

cleave the ketal group.

the ketal group.

diol-3,11,20-trione 20-monoethylene glycol ketal to react with acetamidine according to the manipulative procedure described above in Example 1, part (b), followed by heat ing with dilute acetic acid to cleave the ketal group.

EXAMPLE 76 (a) 2 hydroxymethylene-4-pregnene-7a,12oi-diol-3,20-

dione 20-m0n0ethylene glycol ketal can be prepared by replacement of the 17a-methyl-4-androsten-17B-0l-3-one in Example 4, part (a) by a molar equivalent amount of 4-pregnene-7a,l2a-diol-3,20-dione 20-monoethylene glycol ketal.

(b) 7a,12a-dihydroxy 20 0x0 4 pregneno [3.2-d1- 2'-methylpyrimidine can be prepared by causing 2-hydroxymethylene 4 pregnene 7a,l2u diol 3,20 dione ZO-monoethylene glycol ketal to react with acetamidine according to manipulative procedure described above in Example 1,- part (b), followed by heating with dilute acetic acid to cleave the ketal group.

EXAMPLE 77 (a) Z-formyl-9a-flu0ro-16zx-methyl 1,4 pregnadiene- 11,8,17a,21-triol-3,20-dione 20-monoethylcne glycol ketal can be prepared by replacement of the 17a-methyl-4- androsten-17B-ol-3-one in Example 4, part (a) by a molar equivalent amount of 9a-fluoro-l6a-rnethyl-1,4-pregnadiene-l1e,17a,21-triol-3,20-dione 20-monoethylene glycol ketal.

(b) 9afluoro-16ot-methyl ]1 3,17oc,2] trihydroxy-ZO- 0x0- (1 ,3)S-pregnatrieno[3.2-d1-2 '-methyl pyrimidine can be prepared by causing 2-formyl-9ot-fluoro-16a-methyl-1, 4-pregnadiene-l1/3,17oz21-triol-3,20-dione 20 monoethylene glycol ketal to react with acetamidine according the manipulative procedure described above in Example 1, part (h), followed by heating with dilute acetic acid to EXAMPLE 79 (a) 2 formyl-6u,9a-difluoro-l,4-prcgnadiene-11BJ7a, 21-tri0l-3,20-di0ne"20-monoethylene glycol ketal can be prepared by replacement of the 17a-methy1-4-androsten- 17,8-01-3-one in Example 4, part (a) by a molar equivalent amount of 6a,9m-difiuoro-1,4-pregnadiene-11fl,17a, 21-triol-3,20-dione ZO-monoethylene glycol ketal.

(b) 6a,9a-diflu0ro-11fl,17a,21-trihydr0xy-20-0xo-(l,3)- 5-pregnatrien0[3.2-d] -2' methylpyrimidine can be prepared by causing 2 formyl 6u,9a difiuoro-1,4-pregnadlellfi-l1B,17ot,21-l1lOl-3,20-dl0ll 20-monoethylene glycol ketal to react with acetamidine according to the manipulative procedure described above in Example 1, part (b), followed by heating with dilute acetic acid to cleave EXAMPLE 80 (a) Z-hydroxymethylene 611,170; dimethylandrostan- 17[3-0l-30ne can be prepared by replacement of the 17amethyl-4-androsten-l7fl-ol-3-one in Example 4, part (a) (b) 4-bromo'- 17a,21 dihydroxy-l1,20-di0xo-4-pregneno[3.2-d]-2-methylpyrimidine can be prepared by causing Z-hydroxymethylene-4bromo-4-pregnene- 17 ,2 1

by a molar equivalent amount of 6a,l7ot-dimethylandro- (b) 6 (1,1 7u-dimethyl-1 7B-lzydroxyandrostano[3.2-d1-2' in Example 1, part (b).

EXAMPLE 8-1 (11) 2 hydroxymethylene-l 7a-pr0pyl 4-andr0sten-1 7B- l-3-0ne can be prepared by replacement of the 17mmethyl-4-andr0sten17,8-ol-3-one in Example 4, part (a) by a molar equivalent amount of 17a-propyl-4-androsten- (b) 17,8 hydroxy 17a propyl 4 androst en*0[3.2 a'] 2' methylpyrimidine [VI; R is H, R is (CH CH R" isCH X is H Z is OH, Y and Y are CH can be' prepared by causing Z-h'ydroxymethylene-I'M-propyl- 4-androsten-17/3-ol-3-one to react with acetamidine according to the manipulative procedure described above EXAMPLE 82 EXAMPLE 83 (a) 2 hydroxymethylene 4 17a propargyl 4 andr0steni-]7B-0l-3-0ne can be prepared by replacement of the 17otmethyl-4-androsten-17B-ol-3-one in Example 4, part (a) by a molar equivalent amount of l7'ot-propargyl- 4-androsten-17p4ol-3-one. i

(-b) 1 75 hydroxy 17a propargyl 4 androsteno- [3.2- d] 2' methylpyrimidine [VI R isH, R is' CHgCH ECH, R is CH ,X is H Z is OH, Yr and Y are, CH can be prepared by causing 2-hydroxyrnethylenel7ot-propargyl-4-androsten-17/3-ol-3-one to; react with aoetamidine according to :themanipulative procedure described above in Example 1, parttb),

, EXAMPLE s4 v (a) 2 hydroxymethyle-ne 17cc propynyl 4, androsten-17fl-0l-3-0ne can be prepared by replacement of the .17a-methyl-4-androstena17,8-ol-3-one in Example 4, part (a) by a molar equivalent amount of 17a-propynyl- -4 anch'osten-17B-ol-3-one.

([1) 17,8 hydroxy 17oz propynyl 4 androsteno- [3.2 -d]-2-methylpyrimtidine [VI;-R is H, R is CECCH3, R is CH X is H Z is OH, Y and Y are CH can be prepared by causing 2-hydroxymethylene-17a-pro- 26 EXAMPLE 86 (a) 2 hydroxymethylene 17cc methyl l9 nor 4- androsten-17l3-ol-3-0ne can be prepared by replacement of the 17wmethyl-4-androsten-17,B-ol-3-one in Example 4, part (a) by a molar equivalent amount of Not-methyl- 19-nor-4-4androsten-17fl-ol-3-one.

(b) 17;? hydroxy 17cc methyl 19 nor 4 andr0szeno[3.2-d]-2'-methylpyrimidine [VI;'R is H, R and R are CH Xtis H Z is OH, Y is H, Y is CH can be prepared by causing 2-'hydroxymethylene17a-methyl- 19vnor-4-androsten-17,8-01-3-one to react with acetamidine according to the manipulative procedure described above in Example 1, part (b).

EXAMPLE 87 id]-2-metlzylpyrimidine [V; R is H, R is CECCHg, R is CH X is H Z is -OH, Y and Y are CH Ican be 1 prepared by causing Z-hydroxymethylene-l7a-propynylr 20 0x0 4 ---pregnert0[3.2 d] 2 pynyl-4-and-rosten-17,8-ol-3-one to react with acetamidine according to the manipulative procedure described above in Example 1, part (b).

p EXAMPLE s5 (a) 2 hydroxymethylene 17a 'propylandrostan- 17fi- 0l3-0ne can be prepared by replacement of the 17otv vmethyl-4-androsten-17,8-01-3-one in Example 4, part (a) by a molar equivalent amount of l7et-propylandrostan- 17,8-o1-3-onel A (17) 17B hydroxy 17a propylandrostanoBJ d]- 1 2-methylpyrimidine '[V; R is H, R is CH CH CH R" [is CH X is H Z is OH, Y arid Y are CH can be prepared by causing 2 liydroxymethylene-17ot propylanhydride in pyridine.

landrostan-17B-ol-3-one to react with acetamidine according to the manipulative procedure described above in Example 1, part, (b).

EXAMPLE 881 (a) 2 -hydr0xymethylene 9a fluoro 4 pregnene- ]1fl,17oz,21 triol 3,20 dione [7,20,20,21 bismethyh enedioxy derivative was prepared from 8.54 g. of 9oc-flll0- rohydrocortisone 17,20;20,21-bismethylenedioxy derivative, 24 ml. of ethyl formate and 1.2 g. of sodium hydride in benzene according to the manipulative procedure described above in Example 4, part (a).

(b) 9a fluoro 1],8,]7oa,2] trihydroxy 20 0x0 L 4- pregnen0[3.2 d] 2 methylpyrimidirie 17,20,202]- bismezhylenedioxy derivative can be prepared by causing 2 hydroxymethylene 9a fluoro 4 pregnene 115,

3,20 dione 17,20;20,2l bismethylenedioxy derivative to react with acetamidine according to the manipulative procedure described above in Example 1, part (b). V

'(c) 2] aeefoxy c fluoro 11/3,]7a dihydroxymethylpyrim'idine can be prepared by treating- 9a fiuoro-11fi,l7a,21-trihydroxy 2O oxo 4 pregneno[3. 2 d] 2 methylperchloric acid in acetic acid to cleave the bismethylenedioxy group and acetylating the product with acetic 'an- M EXAMPLE- 89 I (a) 2 hydroxymethylene 4 pregnene -1 1fi,]7a,2]- trial 3,20 dione 17,20,202] bismethylenedioxy derivative Was prepared from 12.6 g. of hydrocortisone 17,20,202l-bismethylenedioxy derivative, of ethyl formate and 2.2 g. of sodium hydride in benzene according to the manipulative procedure described above in Example 4, part (a).. x

(b) J]/3,17a,21 trihyaroxy 20 0x0 4 pregneno- [3.2 d] 2"- methylpyrimidine17,20,202] bismethyle'nedioxy derivative ean beiprepared by causing 2'-l 1ydroxy 4 pregnene llfl,l7c,21 triol 3,20'-'di0ne 17,20;20,2l-bismethylenedioxy derivative to react with acetamidine according to the manipulative procedure described-above in Example 1, part (b). p

(0-) ,1 113,] 701,21 trihydroxy 20 0x0 4 pregnanc- [3.2 d] 2 methylpyrimidine [V1, R is H,-R is COCH OH, R is CH X is (H-) (OH), Z is OH, Y and Y are CH can be prepared by treating 11,8,17a,21-trihydroxy 2O oxo 4 pregneno[3.2 d] 2' methylpyrimidine 1'7,20; 20,2l-bismethylenedioxy derivative with perchloric acid in acetic acid.

2? EXAMPLE 90 (a) 2 hydroxymethylene 4,4 dimethyl 5 pregnene-3,20-dine 20-m0n0ethylene glycol ketal was prepared from 4,4-dimethyl--pregnene-3,20-dione 20-monoethylene glycol ketal, ethyl formate and sodium hydride in benzene according to the manipulative procedure described above in Example 4, part (a). The product was EXAMPLE 91 17,B-hydr0xy-17a-methyl 1,3,5 estratrieno[3.2-d] -2- .methylpyrimidine can be prepared by heating 17,3-hydroxy 17,6-methyl-19-nor-4-androsteno[3.2-d] -2'-methylpyrimidine with palladium catalyst; or by brornination of the latter compound at the -position by means of N-bromosuccinimide, followed by dehydrobromination by heating with collidine or with lithium chloride in dimethylformamide solution.

The following compounds can also be prepared by application of the procedures described hereinabove to the appropriate starting materials:

EXAMPLE 92 60c fluoro--oxo-4-pregnen0[3.Z-d]-2'-methylpyrimidine from 6u-fluoro-4-pregnene-3,20-dione. 7

EXAMPLE 95 6 fluoro 20 0x0 4,6 pregnadieno[3.2-d] -2'-methylpyrimidine from 6-fluoro-4,6-pregnadiene-3,20-dione.

EXAMPLE 96 17oc-me hyl-17B-hydr0xy-19-n0r 4,9 androstadieno- [3.2-d]-2-methylpyrimidine from 17u-methyl-19-nor-4,9- androstadien-1713-ol-3-one.

EXAMPLE 97 713,17 a-dimethyl-17fi-hydr0xy 4 androstenolfiZ-dl- 2 methylpyrimidine from 7B,17a-dimethy1-4-androsten- 17 8-ol-3-one (713,17a-dimethyltestosterone).

EXAMPLE 98 5 methyl 11fi,17oz,21 trihydroxy 20 oxypregnano- [3.2-d]-2-melhylpyrimidine from 5-methyl-17a,20;20,21-

bismethylenedioxypregnan- 1 1 B-ol-3 -one.

EXAMPLE 99 10a methyl-9fl-H-20-ox0-19-n0r 4,6 pregnadieno- .[3.2-d]-2'-methylpyrimidine from 10a-methy1-9B-H-19- nor-4,6-pregnadiene-3,20-dione.

EXAMPLE 100 10 methyl 96 H 17B hydroxy-Z9-nor-4,6-androsta- 'dieno- [3 .Z-d] -2-methylpyrimidine from 10a-methyl-9p-H- Also within the purview of the invention are pyrimidine derivatives of D-homosteroids. The following such compounds can be prepared by procedures analogous to those described hereinabove:

EXAMPLE 101 17oc-0xa 17 0x0 D h0m0-4-androsteno [3.2-d] -2'- methylpyrimidine from testololactone.

EXAMPLE 102 20-0x0 D h0m0-4-pregnen0[3.2-d] -2'-methylpyrimidine from D-homo-4-pregnene 3,20 dione (D-homoprogesterone) EXAMPLE 103 hydroxy-D-hom 0-4-andr0sten0 [3.2-d] -2 -methylpyrimidine from D-homo-4-androsten-17,6-ol-3-one (D- homotestosterone) EXAMPLE 104 17a-methyl-17B-hydroxy D h0m0andr0stan0[3.2-d]

.2-mathylpyrimidine from 17m-methyl-D-homoandrostan- 17fl-ol3-one.

EXAMPLE 105 906,175 dihydroxyandrostano[3.2-d]-2'-methylpyrimidine from :,17p-dihydroxyandr0stan-3-one.

EXAMPLE 106 90,17fi dihydroxyandroszano[3.2-d] 2' methylpyrimidine can be treated with a solution of hydrogen fluoride in pyridine to give 9oc-fluoro-17B-hydroxyandrostano- [3.2-d]-2'-methylpyrimidine; and the latter can be oxidized with chromium trioxide in pyridine to give 9mfluoro-17-oxoandrostano 3 .2-d] -2-methylpyrimidine.

* EXAMPLE 107 17/3-hydroxy (1,3) andr0stadien0[3.2-d]-2' methylpyrimidine can be prepared from 2-acety1androstan-17fiol-3-one (Example 20(b)) by brominating the latter with bromine in pyridine to give the 2-br0mo derivative, M.P. 1-19.0-121.0 C. (corn), [a] =+163.t (1% in chloroform), dehydrobrominating the latter with collidine to give Z-acetyl-l-androsten-17/8-ol-3-one, followed by reaction with acetamidine in the usual manner.

I claim:

1. A steroido[3.2-d]pyrimidine, the steroid moiety having from seventeen to about twenty-three carbon atoms exclusive of ester radicals and being selected from the group consisting of the estrane, 18-norestrane, androstane, etiocholane, pregnane and allopregnane series; and wherein'the carbon atoms of the pyrimidine moiety are substituted by a member of the group consisting of hydrogen and lower-alkyl.

andY' represents members of the group consisting of hydrogen and methyl; and Z represents a member of the group consisting of hydrogen and hydroxy, Z being restricted to hydroxy when R represents a member of the group consisting of hydrogen, lower-alkyl, lower-alkenyl and lower-alkynyl; and (B) carboxylic acid esters of carbinols thereof, the acyl moieties of said esters having from one to about ten carbon atoms and having a molecular weight less than about 200.

3. A compound selected from the group consisting of (A) compounds having the formula V v Y,

wherein R and R represent members of the group con-p sisting of hydrogen and lower-alkyl; R represents a member of the group consisting of hydrogen, lower-alkyl, lower-alkenyl,lower-alkynyl, acetyl, hydroxyacetyl, 1,2- dihydroxyethyl and l-hydroxyethyl; X represents a member of the group consisting of H (H) (OH) and O; Y and Y represent members of the group consisting of hydrogen and methyl; and Z represents a member of the group consisting of hydrogen and hydroxy, Z being re- 7 stricted to hydroxy when R represents a member of the group consisting of hydrogen, lower-alkyl, lower-alkenyl and .lower-alkynyl; and (B) carboxylic acid esters of carbinols thereof, the acyl moieties of said esters having from one to about ten carbon atoms and having a molecular weight less than about 200. a r

4. I A compound selected from the group consisting of (A) compounds having the formula wherein R and R" represent members of the group consisting of hydrogen and lower-alkyl; R represents a member of the group consisting of hydrogen, lower-alkyl,

lower-alkenyl, lower-alkynyl, acetyl, hydroxyacetyl, 1,2-dihydroxyethyl and l-hydroxyethyl; X represents a member of the group consisting of H (H) (OH) and O; Y and Y represent members of the group consisting of hydrogen and methyl; and Z represents a member of the l 7 group consisting of hydrogen and hydroxy, Z being restrictedto hydroxy when R represents a member of the group consisting of hydrogen, lower-alkyl, lower-alkenyl and lower-alkynyl; and (B) carboxylic acid esters of carbinols thereofithe' acyl moieties of said esters having from one to about ten carbon atoms and having a molecular weight less than about 200.

5. 17/3 hydroxy 17cc methylandrostano[3.2 d] 2 reacting a 2-(l-hydroxyalkylidene)-3oXo-steroid with a member of the group consisting of a lower-alkanoamidine and acid-addition saltsthereof in the presence of a base selected from the group consisting of basic tertiary amines and alkali metal alkoxides, the steroid moiety having from seventeen to about twenty-three carbon atoms exclusive of ester radicals and being selected from the group consisting of the estrane, 18-norestrane,' androstane, etiocholane, pregnane and allopregnane series.

12. The process for preparing a compound selected from the group consisting of (A) compounds having the formula wherein R and R" represent members of the group con- 1 sisting of hydrogen and loweralkyl; R represents a member of the group consisting of hydrogen, lower-alkyl, lower-alkenyl, lower alkynyl, ketalized acetyl, ketalized hydroxyacetyl, 1,2-dihydroxyethyl and l-hydroxyethyl; X represents a member of the group consisting of H (H) (OH) and O; Y and Y represent members of the group consisting of hydrogen and methyl; and Z represents a member of the group consisting of hydrogen and hydroxy,

Z being restricted to hydroxy when R represents a member of the group consisting of hydrogen, lower-alkyl, lower-alkenyl and lower-alkynyl; and (B) carboxylic acid esters of carbinols thereof, the acyl moieties of said esters having from one to about ten carbon atoms and having a molecular weight less than about 200, which comprises reacting a compound having the formula l t Y I wherein R, R, X, Z, Y and Y are identical with their selection above, with a member of the group consisting of a loWer-alkanoamidine and acid-addition salts thereof in the presence of a base selected from the group consisting of basic tertiary amines and alkali metal alkoxides.

13. The process for preparing a' compound selected HO-C from the group consisting of (A) compounds having theformula wherein R and R represent members of the group consisting of hydrogen and lower-alkyl; R represents a member of the group consisting of hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl, ketalized acetyl, ketalized hydroxyacetyl, 1,2-dihydroxyethyl and l-hydroxyethyl; X represents a member of the group consisting of H (H) (OH) and O; Y and Y represent members of the group consisting of hydrogen and methyl; and Z represents a member of the group consisting of hydrogen and hydroxy,

' Z being restricted to hydroxy when R represents a member of the group consisting of hydrogen, lower-alkyl, lower-alkenyl and lower-alkynyl; and (B) carboxylicacid wherein R, R, X, Z, Y and Y are identical with their 15 selection above, with a member of the group consisting of a lower-alkanoamidine and acid addition salts thereof in the presence of a base selected from the group consisting of basic tertiary amines and alkali metal alkoxides.

14. The process for preparing a compound selected 20 from the group consisting of (A) compounds having the formula wherein R and R" represent members of the group consisting of hydrogen and ,lower-alkyl; R represents a member of the group consisting of hydrogen, lower- 32 alkyl, lower-alkenyl, lower-alkynyl', ketalized acetyl, ketalized hydroxyacetyl, 1,2-dihydroxyethyl and l-hydroxyethyl; X represents a member of the group consisting of H (H) (OH) and O; Y and Y represent members of the group consisting of hydrogen and methyl; and Z represents a member of the group consisting of hydrogen and hydroxy, Z being restricted to hydroxy when R represents a member of the group consisting of hydrogen, lower-alkyl, lower-alkenyl and loweralkynyl; and (B) carboxylic acid esters of carbinols thereof, the acyl moieties of said esters having from one to about tencarbon atoms and having a molecular Weight less than about 200, which comprises reacting a compound having the formula 1'2 Y HOC= References Cited in the file of this patent UNITED STATES PATENTS 3,026,317 Ringold et al. Mar. 20, 1962 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,132,137 I May 5, 1964 Raymond 0. Clinton 4 It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, lines 17 to 27, and lines 41 to 51, the lefthand portions of formulas (V) and (VI) should appear as shown below instead of as in the patent:

RLICL N column 16, line 15, for "17B-ol-one", in italics, read 1,76- o-l,- .3one in italics; line 16, for "-17B-ol-one" read -l7B-ol3-one column 19, line 69, for "176-", in italics, read 170cin italics; column 20, line 28, for "6],l7B-", in italics, read -68,l7B in italics; column 22, line 29, for "2-hydroxymethylallopregnane" read Z-hydroxymethyleneallopregnanecolumn 23, line 57, for "[3 L2]-", in italics, read [3.2d] initalics; column 25, line 43, for "CH CHECH" read CH CECH column 26, lines 64 and 65, for "Z-hydroxyfl' read-- 2-hydroxymethylenecolumn 27, line 24, for "l7B-methyl-" read l7amethylcolumn 28, line 6, for "17OL-OX3.-", in italics, read l7a-oxain italics; column 29 line 62, for "methylprimidine" read methylpyrimidine line 63, for "pyrimi" read pyrimidine.--.

Signed and sealed this 20th day of October 1964.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A STEROIDO(3.2-D)PYRIMIDINE, THE STEROID MOIETY HAVING FROM SEVENTEEN TO ABOUT TWENTY-THREE CARBON ATOMS EXCLUSIVE OF ESTER RADICALS AND BEING SELECTED FROM THE GROUP CONSISTING OF THE ESTRANE, 18-NORESTRANE, ANDROSTANE, ETICHOANE, PREGNANE AND ALLOPREGNANE SERIES; AND WHEREIN THE CARBON ATOMS OF THE PYRIMIDINE MOIETY ARE SUBSTITUTED BY A MEMBER OF THE GROUP CONSISTING OF HYDROGEN AND LOWER-ALKYL. 